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Purpose This study aimed to evaluate the potential of podoplanin (PDPN)-targeted alpha-radiotherapy (RIT) for treating malignant mesothelioma. Methods A newly developed anti-PDPN antibody, NZ-16, and a previous anti-PDPN antibody, NZ-12, were assessed. The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing NCI-H226 (H226) mesothelioma cells. The biodistribution of 111In-labeled antibodies was studied in tumor-bearing mice. Tumor volumes and body weights of mice treated with 90Y- and 225Ac-labeled NZ-16 were measured for 56 days. The absorbed doses were estimated on the basis of the biodistribution data. Pathologic analysis of tumors and organs was conducted. Results The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ-12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12. RIT with 225Ac-labeled NZ-16 (11.1 and 18.5 kBq) had a significantly higher antitumor effect than RIT with 90Y-labeled NZ-16 (3.7 MBq; P < 0.01). 225Ac-labeled NZ-16 induced more necrosis compared with 90Y-labeled NZ-16, but the Ki-67 index and apoptosis rate were similar. The estimated absorbed doses were expected to be tolerable in mice. Temporary body weight loss occurred, but recovered within several days. No visible damage to major organs was detected. Conclusion The novel anti-PDPN antibody NZ-16 was a more effective RIT agent than NZ-12. Radiolabeled NZ-16, especially 225Ac-labeled NZ-16, markedly suppressed tumor growth and prolonged survival without inducing severe adverse effects. RIT with radiolabeled NZ-16 is a promising therapeutic option for malignant mesothelioma.

Malignant pleural mesothelioma (MPM) has extremely limited treatment despite a poor prognosis. Moreover, molecular targeted therapy for MPM has not yet been implemented; thus, a new targeted therapy is highly desirable. Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer therapy that combines the specificity of antibodies for targeting tumors with toxicity induced by the photoabsorber after exposure to NIR-light. In this study, we developed a new phototherapy targeting podoplanin (PDPN) for MPM with the use of both NIR-PIT and an anti-PDPN antibody, NZ-1. An antibody-photosensitizer conjugate consisting of NZ-1 and phthalocyanine dye was synthesized. In vitro NIR-PIT-induced cytotoxicity was measured with both dead cell staining and luciferase activity on various MPM cell lines. In vivo NIR-PIT was examined in both the flank tumor and orthotopic mouse model with in vivo real-time imaging. In vitro NIR-PIT-induced cytotoxicity was NIR-light dose dependent. In vivo NIR-PIT led to significant reduction in both tumor volume and luciferase activity in a flank model (p < 0.05, NIR-PIT group versus NZ-1-IR700 group). The PDPN-targeted NIR-PIT resulted in a significant antitumor effect in an MPM orthotopic mouse model (p < 0.05, NIR-PIT group versus NZ-1-IR700 group). This study suggests that PDPN-targeted NIR-PIT could be a new promising treatment for MPM.

A number of standard methods have been proposed to determine the Mode I fracture toughness of rock. They include those based on short rod (SR) specimen, chevron bend (CB) specimen and cracked chevron-notched Brazilian disk (CCNBD) specimen. The semi-circular bend (SCB) specimen has been widely used for fracture toughness determination of geomaterials owing to inherent favourable properties such as its simplicity, minimal requirement of machining and the convenience of testing that can be accomplished by applying 3-point compressive loading using a common laboratory load frame. Use of more than one type of specimen is regarded as appropriate when it is required to measure the fracture toughness of anisotropic materials in different material directions of a rock sample. The objective of this paper is to provide details of the process of development of ISRM Suggested Method for Mode I static fracture toughness determination of rock and other geomaterials using SCB specimen, which was recently approved by ISRM. The details of the development process including the stress intensity factor calibration using the finite element method, improvement of the suggested experimental method including the steps taken to minimise errors, and suggestions to improve the accuracy of results are given.